In order to survive, animals must modify their behavior as they encounter new environmental conditions. To achieve this, the nervous system integrates complex external stimuli and modifies its activity appropriately. Ultimately, plasticity at the level of single neurons enables these changes, and in many cases neuronal and behavioral plasticity is long-lasting. Changes in gene expression have been shown to underlie many forms of long-term plasticity, and disruption of these expression changes and their upstream regulators are associated with neurological disease. Here I propose to take advantage of temperature-dependent neuronal and behavioral plasticity in C. elegans, phenomena that are biologically relevant, easily manipulated, and quantifiable, in order to interrogate the gene expression changes and gene regulatory mechanisms underlying plasticity in vivo. Our lab and others have characterized plasticity of temperature preference behavior in C. elegans. We have established that modulation of the physiology of the single thermosensory neuron pair AFD contributes to behavioral plasticity. We have identified receptor-type guanylyl cyclases as likely thermosensory genes acting in AFD and shown that they are regulated by temperature at the level of transcription. In this proposal I use this single cell plasticity paradigm as an avenue to conduct detailed analyses of gene regulatory systems driving neuronal plasticity and to connect them to animal behavior. First, I describe experiments to identify genome-wide the genes that are differentially expressed in AFD and mediate the dynamic progression of plasticity. Then, I outline a strategy to uncover the molecular regulatory principles that control expression of thermosensory rGCs during temperature-induced plasticity. My proposed project will describe in great detail the gene regulatory pathways driving neuronal plasticity in vivo and link them to behavior. This work will define the relationships among an environmental input, stimulus- induced gene expression, and neuronal plasticity that enables accurate transformation of neuronal output and behavior. Additionally, characterization of gene regulatory pathways that dynamically and precisely control neuronal plasticity may help to explain how they can fail in the context of neurological disease.